Inhibition of ABCC4 potentiates combination beta agonist and glucocorticoid responses in human airway epithelial cells

• Published in: Journal of allergy and clinical immunology 2018-03, Vol.141 (3), p.1127-1130.e5
• Main Authors: Huff, Ryan D., Rider, Christopher F., Yan, Dong, Newton, Robert, Giembycz, Mark A., Carlsten, Chris, Hirota, Jeremy A.
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Asthma; Epithelial cells; Experiments; Gene expression; Hispanic people; Human behavior; Inflammation; Kinases; Mucous membrane; Particulate matter; Proteins; Respiratory tract; Smooth muscle; Software; Uric acid
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2017.10.011

To the Editor: The Global Initiative for Asthma guidelines recommend the use of relievers and controllers to promote airway smooth muscle relaxation and attenuate inflammation, respectively.1 β2-Adrenoceptor agonists are the mainstay reliever therapy and promote rapid bronchodilation by activating the classical cyclic adenosine monophosphate (cAMP)/adenylyl cyclase/cAMP-dependent protein kinase (PKA) cascade.2 In contrast, glucocorticoids suppress lung inflammation by modulating gene expression.3 Long-acting β2-adrenoceptor agonists and glucocorticoids are clinically superior when used in combination relative to either drug alone as a monotherapy and synergize in the regulation of many anti-inflammatory genes.4 It has been proposed that strategies aimed to increase intracellular cAMP beyond existing combination therapies may provide improved management of asthma symptoms.4 We have recently demonstrated that human airway epithelial cells express the ATP binding cassette transporter C4 (ABCC4; formerly known as multidrug resistance protein 4) and that inhibition of ABCC4 is associated with decreased extracellular transport of cAMP.5 In addition to cAMP, human airway epithelial cells transport uric acid via ABCC4 to link innate and adaptive immune responses important in asthma.5 ABCC4 can also transport prostaglandins and impact mucociliary clearance via an autocrine/paracrine mechanism in human airway epithelial cells.6 In a human embryonic kidney cell line, ABCC4 has been shown to transport leukotrienes,7 although this has not been confirmed in human airway epithelial cells. [...]we explored the functional consequences of ABCC4 inhibition on the ability of combination glucocorticoid/cAMP-elevating agents to regulate inflammatory responses from a human airway epithelial cell line. [...]the clinical management of chronic respiratory diseases includes the use of combination therapies to attenuate inflammation and increase intracellular cAMP concentrations. Asthma Sex Age (y) Weight (kg) Height (cm) Ethnicity IHC Gene expression N M 20 86 185 White Y Y N M 22 112 193 White Y Y N F 19 87 165 White Y N F 20 72 165 White Y Y N M 24 82 175 Hispanic Y N M 12 48 160 White Y N F 42 90 178 White Y Y F 8 31 117 Hispanic Y Y M 11 65 153 White Y Y F 21 55 170 White Y Y M 11 69 170 White Y Y F 26 92 168 White Y Y M 10 43 158 White Y Y M 25 103 185 Hispanic Y Y Y M 23 53 152 Hispanic Y Y 1 H.K. Reddel, E.D. Bateman, A. Becker, L.P. Boulet, A.A. Cruz, J.M. Drazen, A summary